Carvedilol

Carvedilol is an antihypertensive belonging to a Nonselective beta-adrenergic antagonist.

Carvedilol is used in the treatment of chronic therapy of heart failure with reduced ejection fraction (HFrEF), hypertension, and left ventricular dysfunction following myocardial infarction (MI) in clinically stable patients. It is also used in the treatment of stable angina, atrial fibrillation, cirrhotic esophageal variceal bleeding prophylaxis, and ventricular arrhythmias.

Carvedilol is rapidly and extensively absorbed from the gastrointestinal tract and undergoes a first-pass effect. The rate of absorption is delayed with food with absolute bioavailability of Approx 25-35% (immediate release). It is distributed into extravascular tissues and is highly lipophilic. Plasma protein binding is >98% primarily to albumin with the volume of distribution: 115 L. It is extensively metabolized in the liver via CYPD26 and CYP2C9 enzymes by glucuronidation and aromatic ring oxidation, and oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. It gets excreted primarily via feces; urine (<2%, unchanged) with an elimination half-life of 7-10 hours.

The common side effects are Hypotension with or without syncope and bradycardia. Blood and lymphatic system disorders: Anaemia. Cardiac disorders: Dyspnoea, pulmonary edema, etc.

Carvedilol is available in the form of dosage forms such as tablets, and capsules.

Carvedilol is available in Canada, Denmark, Spain, Sweden, India, the U.S.A

Carvedilol works by slowing down the heart rate and making it easier for the heart to pump blood around the body. It also works like an alpha blocker to widen some of the blood vessels. This helps lower blood pressure.

It works directly on the heart tissue and will slow the nerve impulses in the heart. This helps keep the heart rhythm normal.

The onset of Action of Carvedilol was within 1 to 2 hours.

The Duration of Action of Carvedilol was 7-10 hr

The Tmax was about Approx 1 hour (immediate release); approx 5 hours (extended release).

Carvedilol is available in the form of a dosage form such as tablets and capsules.

Tablets and capsules: Carvedilol tablets and capsules should be taken orally with or without food.

Carvedilol is used in the treatment of chronic therapy of heart failure with reduced ejection fraction (HFrEF), hypertension, and left ventricular dysfunction following myocardial infarction (MI) in clinically stable patients. It is also used in the treatment of stable angina, atrial fibrillation, cirrhotic esophageal variceal bleeding prophylaxis, and ventricular arrhythmias.

Carvedilol is used in the treatment of chronic therapy of heart failure with reduced ejection fraction (HFrEF), hypertension, and left ventricular dysfunction following myocardial infarction (MI) in clinically stable patients. It is also used in the treatment of stable angina, atrial fibrillation, cirrhotic esophageal variceal bleeding prophylaxis, and ventricular arrhythmias.

Carvedilol inhibits exercise-induced tachycardia through its inhibition of beta-adrenoceptors. Carvedilol's action on alpha-1 adrenergic receptors relaxes the smooth muscle in the vasculature, leading to reduced peripheral vascular resistance and an overall reduction in blood pressure.

Carvedilol is used in the treatment of chronic therapy of heart failure with reduced ejection fraction (HFrEF), hypertension, and left ventricular dysfunction following myocardial infarction (MI) in clinically stable patients. It is also used in the treatment of stable angina, atrial fibrillation, cirrhotic esophageal variceal bleeding prophylaxis, and ventricular arrhythmias.

Heart Failure

Carvedilol is indicated for the treatment of mild-to-severe chronic heart failure of ischemic or cardiomyopathic origin, usually in addition to diuretics, ACE inhibitors, and digitalis, to increase survival and, also, to reduce the risk of hospitalization

Hypertension

Carvedilol is indicated for the management of essential hypertension. It can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.

Left Ventricular Dysfunction Following Myocardial Infarction

Carvedilol is indicated to reduce cardiovascular mortality in clinically stable patients who have survived the acute phase of myocardial infarction and have a left ventricular ejection fraction of less than or equal to 40% (with or without symptomatic heart failure)

Although not approved, there have been certain off-label use documented for Carvedilol which includes:

Chronic stable angina

Adult: Initially, 12.5 mg bid for 2 days, increased to 25 mg bid. May gradually increase further at intervals of at least two weeks, if necessary. Max: 100 mg daily in 2 divided doses.

Elderly: Initially, 12.5 mg bid for 2 days, continued to 25 mg bid.

Although not approved there have been certain off-label use documented for Carvedilol which includes:-

Nonsustained ventricular tachycardia or ventricular premature beats, symptomatic:

Immediate release: Oral: Initial: 3.125 mg twice daily; titrate as needed based on response and tolerability up to 25 mg twice daily

Variceal hemorrhage prophylaxis, primary (alternative agent):

Immediate release: Oral: Initial: 3.125 mg twice daily or 6.25 mg once daily; titrate according to resting heart rate (target 55 to 60 beats per minute) while maintaining blood pressure (eg, systolic blood pressure ≥90 mm Hg) to a maximum dose of 6.25 mg twice daily.

The dosage and the duration of treatment should be as per the clinical judgment of the treating physician.

Carvedilol is available in various dosage strengths :-3.125 mg; 6.25 mg; 12.5 mg; 25 mg; 10 mg; 20 mg; 40 mg; 80 mg

Carvedilol is available in the form of a dosage form such as tablets, and capsules.

Carvedilol is used in the treatment of chronic therapy of heart failure with reduced ejection fraction (HFrEF), hypertension, and left ventricular dysfunction following myocardial infarction (MI) in clinically stable patients. It is also used in the treatment of stable angina, atrial fibrillation, cirrhotic esophageal variceal bleeding prophylaxis, and ventricular arrhythmias.

Heart Failure: Choose plenty of fresh fruits and vegetables.

They contain only small amounts of salt. Choose foods that are low in salts, such as fresh meats, poultry, fish, dry and fresh legumes, eggs, milk, and yogurt. Plain rice, pasta, and oatmeal are good low-sodium choices.

Hypertension: It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

Ventricular arrhythmias: Diets high in processed foods, such as fast food, and items high in added sugar, like soda and sugary baked goods, have been linked to increased heart disease risk.

Drinking too much alcohol can increase the risk of developing AFib.It may also trigger AFib episodes in people who already have AFib, especially if patients have existing cardiovascular disease or diabetes.

The dietary restriction should be individualized as per the patient's requirements.

Carvedilol may be contraindicated in the following

Absolute contraindications for the use of Carvedilol include severe hypotension, second or third-degree AV block, sick sinus syndrome, and severe bradycardia in the absence of a functional pacemaker, severe decompensated heart failure requiring inotropic support, and a history of a serious hypersensitivity reaction. Clinicians should use caution in a patient with a history of asthma or reactive airway disease, and the recommendation is to avoid use in patients with active wheezing due to its beta-blocking properties.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

• Cessation of Therapy

Patients with coronary artery disease, who are being treated with Carvedilol, should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in angina patients following the abrupt discontinuation of therapy with ß-blockers. The last 2 complications may occur with or without preceding exacerbation of angina pectoris. As with other ß-blockers, When discontinuation of Carvedilol is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. Carvedilol should be discontinued over 1 to 2 Weeks whenever possible. If angina worsens or acute coronary insufficiency develops, it is recommended that Carvedilol be promptly reinstituted,at least temporarily. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue Carvedilol therapy abruptly even in patients treated only for hypertension or heart failure.

• Bradycardia

In clinical trials, Carvedilol caused bradycardia in about 2% of hypertensive patients, and 6.5% of myocardial infarction patients with left ventricular dysfunction. If the pulse rate drops below 55 beats/minute, the dosage should be reduced.

• Hypotension

Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive patients, primarily following the initial dose or at the time of dose increase, and was a cause for discontinuation of therapy in 1% of patients. In the Carvedilol study of survivors of acute myocardial infarction, hypotension or postural hypotension occurred in 20.2% of patients receiving Carvedilol compared to 12.6% of placebo patients. Syncope was reported in 3.9% and 1.9% of patients, respectively. These events were a cause for discontinuation of therapy in 2.5% of patients receiving Carvedilol, compared to 0.2% of placebo patients. starting with a low dose, administration with food and gradual up-titration should decrease the likelihood of syncope or excessive hypotension. During the initiation of therapy, the patient should be cautioned to avoid situations such as driving or hazardous tasks, where injury could result should syncope occur.

• Heart Failure/Fluid Retention

Worsening heart failure or fluid retention may occur during the up-titration of Carvedilol. If such symptoms occur, diuretics should be increased and the carvedilol dose should not be advanced until clinical stability resumes. occasionally it is necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to, Carvedilol.

• Non-allergic Bronchospasm

Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in general, not receive ß-blockers. Carvedilol may be used with caution, however, in patients who do not respond to or cannot tolerate, other antihypertensive agents. It is prudent, if Carvedilol is used, to use the smallest effective dose so that inhibition of endogenous or exogenous ß-agonists is minimized. In clinical trials, patients with the bronchospastic disease were enrolled if they did not require Oral or inhaled medication to treat their bronchospastic disease. In such patients, it is recommended that Carvedilol be used with caution. The dosing recommendations should be followed closely and the dose should be lowered if any evidence of bronchospasm is observed during up-titration.

• Glycemic Control in Type 2 Diabetes

In general, ß-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective ß-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities.

• Peripheral Vascular Disease

ß-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.

• Deterioration of Renal Function

Rarely, the use of Carvedilol in patients with heart failure has resulted in deterioration of renal function. Patients at risk appear to be those with low blood pressure (systolic blood pressure <100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. Renal function returned to baseline when Carvedilol was stopped. In patients with these risk factors, it is recommended that renal function be monitored during up-titration of Carvedilol and the drug discontinued or the dosage reduced if worsening of renal function occurs.

• Anesthesia and Major Surgery

If treatment with Carvedilol is to be continued perioperatively, particular care should be taken when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used for information on the treatment of bradycardia and hypertension.

• Thyrotoxicosis

ß-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia.

Abrupt withdrawal of ß-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.

• Pheochromocytoma

In patients with pheochromocytoma, an α-blocking agent should be initiated prior to the use of any ß-blocking agent. Although Carvedilol has both α- and ß-blocking pharmacologic activities, there has been no experience with its use in this condition. Therefore, caution should be taken in the administration of Carvedilol to patients suspected of having pheochromocytoma.

• Prinzmetal’s Variant Angina

Agents with nonselective ß-blocking activity may provoke chest pain in patients with prinzmetal's variant angina. There has been no clinical experience with Carvedilol in these patients although the α-blocking activity may prevent such symptoms. However, caution should be taken in the administration of Carvedilol to patients suspected of having Prinzmetal's variant angina.

• Risk of Anaphylactic Reaction

While taking ß-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenges, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Alcohol consumption with Carvedilol may increase the risk of low blood pressure and cause adverse effects, such as Dizziness, fainting, light-headedness, or headache.

Carvedilol use in breastfeeding patients is not recommended.

Pregnancy Category C.

Studies performed in pregnant rats and rabbits given Carvedilol revealed increased post-implantation loss in rats at doses of 300 mg/kg/day (50 times the MRHD as mg/m2) and in rabbits at doses of 75 mg/kg/day (25 times the MRHD as mg/m2). In the rats, there was also a decrease in fetal body weight at the maternally toxic dose of 300 mg/kg/day (50 times the MRHD as mg/m2), which was accompanied by an elevation in the frequency of fetuses with delayed skeletal development (missing or stunted 13th rib). In rats the no-observed-effect level for developmental toxicity was 60 mg/kg/day (10 times the MRHD as mg/m2); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/m2). There are no adequate and well-controlled studies in pregnant women. Carvedilol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Avoid potassium, sodium, calcium and magnesium-rich foods. This combination may reduce or negate Carvedilol's effect in reducing blood pressure. Grapefruit juice: The interaction of grapefruit juice with Carvedilol increases the blood levels of the drug.

The adverse reactions related to molecule Carvedilol can be categorized as

• Common Adverse effects:

Hypotension with or without syncope, bradycardia. Blood and lymphatic system disorders: Anaemia.

• Less Common adverse effects:

Asthenia, fatigue. Infections and infestations: Bronchitis. Metabolism and nutrition disorders: Oedema, hypervolaemia, weight gain, hypercholesterolaemia, hyperglycaemia, hypoglycaemia. Musculoskeletal and connective tissue disorders: Pain in extremities, arthralgia.

• Rare adverse effects:

Dizziness, headache. Psychiatric disorders: Depression. Renal and urinary disorders: Micturition disorders, abnormal renal function, renal failure. Vascular disorders: Orthostatic hypotension, peripheral vascular disease.

The clinically relevant drug interactions of Carvedilol is briefly summarized here.

• Additive effect with Ca channel blockers (e.g., diltiazem, verapamil), amiodarone, MAO inhibitors, reserpine, guanfacine, methyldopa. May increase atrioventricular conduction time and decrease heart rate with digitalis glycosides.
• Increased serum concentrations of ciclosporin. Increased hypoglycaemic effect of insulin and oral antidiabetics. May cause synergistic, negative inotropic and hypotensive effect with anaesthetics.
• Serum concentration may be reduced by CYP450 inducers (e.g. rifampicin, barbiturates) or increased by CYP450 inhibitors (e.g. ketoconazole, cimetidine, fluoxetine, haloperidol, erythromycin). Increased vasoconstriction effect with ergotamine.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Symptoms: Severe hypotension, bradycardia, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, vomiting, disturbed consciousness and generalised seizures.

Management: Initiate supportive treatment. Monitor vital parameters. Administer atropine IV for excessive bradycardia. In the case of drug resistant bradycardia, initiate pacemaker therapy. To support ventricular function, administer glucagon IV or sympathomimetics (e.g. dobutamine, isoprenaline). For peripheral vasodilation, administer norepinephrine with continuous monitoring of the circulation. For bronchospasm, administer β-sympathomimetics (aerosol or IV) or aminophylline via slow IV inj or infusion. Slow IV inj of diazepam or clonazepam may be given for seizures

Pharmacodynamics:

• Carvedilol is a nonselective β-blocker. It reduces peripheral vascular resistance by selective α1 receptor blockade and suppresses the renin-angiotensin system through nonselective β-blockade. Carvedilol has weak membrane stabilizing properties and has no intrinsic sympathomimetic activity.

Pharmacokinetics:

• Absorption:

Rapidly and extensively absorbed from the gastrointestinal tract, undergoes first pass effect. Rate of absorption is delayed with food. Absolute bioavailability: Approx 25-35% (immediate release). Time to peak plasma concentration: Approx 1 hour (immediate release); approx 5 hours (extended-release).

• Distribution:

Distributed into extravascular tissues and is highly lipophilic. Plasma protein binding: >98% primarily to albumin. The volume of distribution: 115 L.

• Metabolism:

Extensively metabolized in the liver via CYPD26 and CYP2C9 enzymes by glucuronidation and aromatic ring oxidation, oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation.

• Excretion:

Primarily via feces; urine (<2%, unchanged). Elimination half-life: 7-10 hours

1. https://reference.medscape.com/drug/coreg-cr-carvedilol-342357
2. https://www.mims.com/india/drug/info/carvedilol?type=full&mtype=generic
3. https://www.nhs.uk/medicines/carvedilol/
4. https://go.drugbank.com/drugs/DB01136
5. https://www.ncbi.nlm.nih.gov/books/NBK534868/